Acute Pain
Conditions
Keywords
Pharmacogenetic, CYP2D6, CYP2C19
Brief summary
This study is comprised of three separate pharmacogenetic trials grouped into a single protocol due to similarities in the intervention, the hypotheses, and the trial design. The three trials are the Acute Pain Trial, the Chronic Pain Trial, and the Depression Trial. Participants can enroll in only one of the three trials. All three trials were registered on ClinicalTrials.gov under NCT04445792. In July 2023 each of the three treatment trials was registered under a separate NCT# and NCT04445792 was converted to a screening record per recent guidance on master protocol research programs (MPRPs). This record is specific to the Acute Pain Trial within the ADOPT-PGx protocol. The Acute Pain Trial is a prospective, multicenter, two arm randomized pragmatic trial. Participants meeting eligibility criteria will be randomly assigned to either immediate pharmacogenetic testing and genotype-guided post-surgical opioid therapy (Intervention arm) or standard care and pharmacogenetic testing after 6 months (Control arm). The investigators will test the hypothesis that pharmacogenetic testing and genotype guided pain management therapy improves pain control after surgery in participants who's body processes some pain medicines slower than normal.
Detailed description
Pain and depression are conditions that impact substantial proportions of the US population. Finding safe and effective drug therapies for both conditions is challenging. In the case of treatment for acute and chronic pain, the challenge is finding effective therapy while minimizing adverse effects or opioid addiction (and the ensuing consequences). For depression, there are few clinically relevant predictors of successful treatment leading to multiple trials of inadequate therapy for some patients. Both opioid and antidepressant prescriptions can be guided by pharmacogenetics (PGx) data based on existing guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC). This study is designed to evaluate the impact of pharmacogenetic testing and genotype-guided pain or anti-depressant therapy on pain control or depression symptoms in a pragmatic setting. The rationale for examining a genotype-guided approach to acute and chronic pain management is based on the importance of CYP2D6 for the bioactivation of tramadol, codeine, and hydrocodone and data from a pilot study supporting improved pain control in intermediate and poor CYP2D6 metabolizers in the genotype-guided arm who are taking these drugs at baseline. Similarly, the rationale for examining a genotype-guided approach to depression medication therapy is based on the demonstrated role of CYP2D6 in the bio inactivation and CYP2C19 oxidation of select, commonly used SSRIs. Secondly, data from industry sponsored trials support the hypothesis of improved depression symptom control in a genotype-guided arm. Study objectives: Determine if a genotype-guided approach to acute post-surgical pain therapy leads to improved pain control compared to usual care, as defined by a decrease in the SIA score. Secondarily, The investigators will evaluate whether this approach leads to reduced use of DEA Schedule II opioids and reduced pain intensity.
Interventions
Genetic testing of CYP2D6 and CYP2C19
Prescribing recommendations to the provider based on the pharmacogenetic testing results
Sponsors
Duke University
National Human Genome Research Institute (NHGRI)
University of Florida
Vanderbilt University Medical Center
Indiana University School of Medicine
Icahn School of Medicine at Mount Sinai
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Immediate vs. delayed pharmacogenetic testing and genotype-guided pain or depression therapy
Eligibility
Sex/Gender
ALL
Age
8 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Acute Pain Trial * Age ≥ 8 years * English speaking or Spanish speaking * Elective/planned surgery types with planned or anticipated to be treated with tramadol, hydrocodone, or codeine pain management at an enrolling site, which may include orthopedic surgeries (e.g. arthroplasty, spine, etc.), open abdominal surgery, or cardiothoracic surgery and others
Exclusion criteria
Trial-wide: * Life expectancy less than 12 months * Are too cognitively impaired to provide informed consent and/or complete study protocol * Are institutionalized or too ill to participate (i.e. mental or nursing home facility or incarcerated) * Have a history of allogeneic stem cell transplant or liver transplant * People with prior clinical pharmacogenetic test results for genes relevant for the study in which they will enroll (CYP2D6 for the pain studies and CYP2D6 or CYP2C19 for depression) or already enrolled in an ADOPT PGx trial Acute Pain Trial * Undergoing a laparoscopic surgery * Receiving chronic opioid therapy, defined as use of opioids on most days for \>3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 10 Day Silverman Integrated Analgesic Assessment (SIA) Score | Day of surgery (baseline) to 10 days post surgery | A composite measure of pain and opioid usage, the Silverman Integrated Analgesic Assessment (SIA) score, at 10 days post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75. The SIA has a total score range of -200 to 200, where a higher score corresponds with higher pain and opioid use. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 10 Day Pain Intensity as Measured by the PROMIS Numeric Pain Rating Scale | 10 days post-surgery | PROMIS (Patient-Reported Outcomes Measurement Information System) Numeric Pain Rating Scale Pain intensity at 10 days post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75. Pain was measured on a scale of 0-10, where higher scores correspond to higher levels of pain. |
| Post-surgery Opioid Usage, Measured in Milligrams of Morphine Equivalents (MME) Per Day | Day of surgery (baseline) to 10 days post surgery | Opioid usage from surgery to 10 days post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75. |
| 3 Month Prescription Pain Medication Misuse | 3 months post surgery | The 7-item PROMIS Prescription Pain Medication Misuse questionnaire assesses the extent to which participants experience medication misuse symptoms over the past 3 months using a 5-point Likert scale. The 7 questions are converted to a raw score, ranging from 7 to 35. Raw scores are converted to T-scores using the PROMIS conversion tables and range from 36.3 to 55.8. Higher scores reflect greater medication misuse. |
| 1 Month PROMIS Mobility Score | 1 month post surgery | PROMIS mobility score at 1 month post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75 in the adult population only. The score ranges from 15 to 75, where a higher score corresponds to higher mobility. |
| Number of Participants With Opioid Persistence | 3-6 months post-surgery, assessed at 6 months | Opioid persistence defined as a filled prescription for an opioid medication 3-6 months post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75. |
| Participants With Drug-Gene Concordance | Within 10 days post-surgery | Drug-Gene Concordance defined as an agreement between the Pharmacogenomics (PGx) Test and the prescribed opioids post surgery for pain management in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75 |
Countries
United States
Contacts
STUDY_DIRECTORHrishikesh Chakraborty
Duke University
PRINCIPAL_INVESTIGATORLarisa H. Cavallari, PharmD
University of Florida
PRINCIPAL_INVESTIGATORJulie A. Johnson, PharmD
Ohio State University
Participant flow
Recruitment details
This record is specific to the Acute Pain Trial within the ADOPT PGx protocol. It only contains the participants consented to the Acute Pain Trial.
Participants by arm
| Arm | Count |
|---|---|
| Acute Pain - Immediate PGx Testing Immediate genetic testing of CYP2D6 and clinical decisions support for pain management prescribing to the healthcare provider
Pharmacogenetic testing: Genetic testing of CYP2D6 and CYP2C19
Clinical decisions support: Prescribing recommendations to the provider based on the pharmacogenetic testing results | 801 |
| Acute Pain - Delayed PGx Testing Delayed genetic testing of CYP2D6 and return of results after the conclusion of the 6-month follow-up period
Pharmacogenetic testing: Genetic testing of CYP2D6 and CYP2C19 | 801 |
| Total | 1,602 |
Baseline characteristics
| Characteristic | Acute Pain - Delayed PGx Testing | Total | Acute Pain - Immediate PGx Testing |
|---|---|---|---|
| Age, Continuous | 61.8 years STANDARD_DEVIATION 13.1 | 62.3 years STANDARD_DEVIATION 12.6 | 62.4 years STANDARD_DEVIATION 14.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 97 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 739 Participants | 1492 Participants | 753 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 3 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 8 Participants | 8 Participants |
| Race/Ethnicity, Customized Race Black or African American | 29 Participants | 51 Participants | 22 Participants |
| Race/Ethnicity, Customized Race More than one race | 3 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 2 Participants | 8 Participants | 6 Participants |
| Race/Ethnicity, Customized Race Other | 55 Participants | 102 Participants | 6 Participants |
| Race/Ethnicity, Customized Race White | 134 Participants | 1223 Participants | 139 Participants |
| Region of Enrollment United States | 801 Participants | 1602 Participants | 801 Participants |
| Sex: Female, Male Female | 122 Participants | 238 Participants | 116 Participants |
| Sex: Female, Male Male | 312 Participants | 619 Participants | 307 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 801 | 2 / 801 |
| other Total, other adverse events | 0 / 801 | 0 / 801 |
| serious Total, serious adverse events | 0 / 801 | 0 / 801 |
Outcome results
Primary
10 Day Silverman Integrated Analgesic Assessment (SIA) Score
A composite measure of pain and opioid usage, the Silverman Integrated Analgesic Assessment (SIA) score, at 10 days post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75. The SIA has a total score range of -200 to 200, where a higher score corresponds with higher pain and opioid use.
Time frame: Day of surgery (baseline) to 10 days post surgery
Population: Modified intent to treat (mITT) population, consisting of participants who completed their surgery and have a genotypic or phenoconverted CYP2D6 activity score ≤ 0.75.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acute Pain - Immediate PGx Testing (Modified Intent-to-treat, mITT) | 10 Day Silverman Integrated Analgesic Assessment (SIA) Score | 1.4 score on a scale | Standard Deviation 95.9 |
| Acute Pain - Delayed PGx Testing (Modified Intent-to-treat, mITT) | 10 Day Silverman Integrated Analgesic Assessment (SIA) Score | -1.4 score on a scale | Standard Deviation 93.1 |
p-value: 0.795795% CI: [-18.3, 23.8]t-test, 2 sided
Secondary
10 Day Pain Intensity as Measured by the PROMIS Numeric Pain Rating Scale
PROMIS (Patient-Reported Outcomes Measurement Information System) Numeric Pain Rating Scale Pain intensity at 10 days post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75. Pain was measured on a scale of 0-10, where higher scores correspond to higher levels of pain.
Time frame: 10 days post-surgery
Population: Modified intent to treat (mITT) population, consisting of participants who completed their surgery and have a genotypic or phenoconverted CYP2D6 activity score ≤ 0.75.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acute Pain - Immediate PGx Testing (Modified Intent-to-treat, mITT) | 10 Day Pain Intensity as Measured by the PROMIS Numeric Pain Rating Scale | 5.2 score on a scale | Standard Deviation 2.2 |
| Acute Pain - Delayed PGx Testing (Modified Intent-to-treat, mITT) | 10 Day Pain Intensity as Measured by the PROMIS Numeric Pain Rating Scale | 5.1 score on a scale | Standard Deviation 2.3 |
p-value: 0.825595% CI: [-0.4, 0.5]t-test, 2 sided
Secondary
1 Month PROMIS Mobility Score
PROMIS mobility score at 1 month post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75 in the adult population only. The score ranges from 15 to 75, where a higher score corresponds to higher mobility.
Time frame: 1 month post surgery
Population: Modified intent to treat (mITT) population, consisting of participants who completed their surgery and have a genotypic or phenoconverted CYP2D6 activity score ≤ 0.75 in adults only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acute Pain - Immediate PGx Testing (Modified Intent-to-treat, mITT) | 1 Month PROMIS Mobility Score | 40.4 score on a scale | Standard Deviation 16.6 |
| Acute Pain - Delayed PGx Testing (Modified Intent-to-treat, mITT) | 1 Month PROMIS Mobility Score | 39.4 score on a scale | Standard Deviation 17.2 |
p-value: 0.601295% CI: [-2.7, 4.7]t-test, 2 sided
Secondary
3 Month Prescription Pain Medication Misuse
The 7-item PROMIS Prescription Pain Medication Misuse questionnaire assesses the extent to which participants experience medication misuse symptoms over the past 3 months using a 5-point Likert scale. The 7 questions are converted to a raw score, ranging from 7 to 35. Raw scores are converted to T-scores using the PROMIS conversion tables and range from 36.3 to 55.8. Higher scores reflect greater medication misuse.
Time frame: 3 months post surgery
Population: Modified intent to treat (mITT) population, consisting of participants who completed their surgery and have a genotypic or phenoconverted CYP2D6 activity score ≤ 0.75 who indicated having a prescription for pain medication in the past 3 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Acute Pain - Immediate PGx Testing (Modified Intent-to-treat, mITT) | 3 Month Prescription Pain Medication Misuse | 38.5 T-score | Standard Deviation 3.8 |
| Acute Pain - Delayed PGx Testing (Modified Intent-to-treat, mITT) | 3 Month Prescription Pain Medication Misuse | 39.2 T-score | Standard Deviation 4.5 |
p-value: 0.24895% CI: [-1.9, 0.5]t-test, 2 sided
Secondary
Number of Participants With Opioid Persistence
Opioid persistence defined as a filled prescription for an opioid medication 3-6 months post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75.
Time frame: 3-6 months post-surgery, assessed at 6 months
Population: Modified intent to treat (mITT) population, consisting of participants who completed their surgery and have a genotypic or phenoconverted CYP2D6 activity score ≤ 0.75.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Acute Pain - Immediate PGx Testing (Modified Intent-to-treat, mITT) | Number of Participants With Opioid Persistence | 24 Participants |
| Acute Pain - Delayed PGx Testing (Modified Intent-to-treat, mITT) | Number of Participants With Opioid Persistence | 21 Participants |
p-value: 0.7528Chi-squared
Secondary
Participants With Drug-Gene Concordance
Drug-Gene Concordance defined as an agreement between the Pharmacogenomics (PGx) Test and the prescribed opioids post surgery for pain management in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75
Time frame: Within 10 days post-surgery
Population: Modified intent to treat (mITT) population, consisting of participants who completed their surgery and have a genotypic or phenoconverted CYP2D6 activity score ≤ 0.75.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Acute Pain - Immediate PGx Testing (Modified Intent-to-treat, mITT) | Participants With Drug-Gene Concordance | 112 Participants |
| Acute Pain - Delayed PGx Testing (Modified Intent-to-treat, mITT) | Participants With Drug-Gene Concordance | 47 Participants |
p-value: <0.0001Chi-squared
Secondary
Post-surgery Opioid Usage, Measured in Milligrams of Morphine Equivalents (MME) Per Day
Opioid usage from surgery to 10 days post-surgery in participants who have a genotypic or pheno-converted CYP2D6 activity score ≤ 0.75.
Time frame: Day of surgery (baseline) to 10 days post surgery
Population: Modified intent to treat (mITT) population, consisting of participants who completed their surgery and have a genotypic or phenoconverted CYP2D6 activity score ≤ 0.75.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Acute Pain - Immediate PGx Testing (Modified Intent-to-treat, mITT) | Post-surgery Opioid Usage, Measured in Milligrams of Morphine Equivalents (MME) Per Day | 10.0 MME/day |
| Acute Pain - Delayed PGx Testing (Modified Intent-to-treat, mITT) | Post-surgery Opioid Usage, Measured in Milligrams of Morphine Equivalents (MME) Per Day | 8.9 MME/day |
p-value: 0.9054Wilcoxon (Mann-Whitney)